By one measure, delivery of therapeutic medicaments generated $122.3 billion in 2012 and will grow to $198.4 billion by 2017. Growth in the market for drug delivery technology provides participants with opportunities to create new ways to deliver increasingly potent and specific therapeutics. Polyethylene glycol (PEG) remains the only synthetic polymer used in commercial products as a stealth drug delivery vehicle because it is substantially biocompatible, and it prolongs blood circulation times for therapeutic carriers. PEG is also associated with hazardous side-effects including immunological responses that can lead to increased blood clotting and embolism, nonspecific recognition by the immune system, and hypersensitivity reactions. These side-effects may be intensified by the non-biodegradability of PEG. Therefore, there is a need in the drug delivery industry for a versatile delivery vehicle for therapeutics that has fewer side-effects.
Polythioaminals are promising substitutes for PEG as therapeutic deliver vehicles. Polythioaminals are polymers that have the general structure
where R1 and R2 are organic or hetero-organic species. It has been shown that polythioaminals having the above structure may be made by reacting an N-substituted hexahydrotriazine with a dithiol, as follows:
Subsequent reactions may replace the hydrogen atoms at the end of the thioaminal polymer with thiol-reactive groups.
The reaction above generates a byproduct amine R2—NH2. As the reaction proceeds, concentration of the byproduct amine grows to an extent that limits progress of the reaction to high degrees of polymerization. If the byproduct amine is not removed, molecular weight of the polymer generally does not grow above about 2,000 Daltons. If the reaction is performed at elevated temperature, volatile byproduct amines may be vaporized to drive the reaction to higher molecular weight. Thioaminal polymers tend to decompose, however, at temperatures much above about 200° C., so use of such methods to increase molecular weight is limited.
Broadly applicable methods of increasing molecular weight of thioaminal polymers are needed.